The receptor tyrosine kinases represent a superfamily of transmembrane proteins that relay signals from the extracellular environment into the cell. The signals are conveyed by ligands which bind the extracellular domains of these kinases, thereby activating a signaling pathway. In this superfamily, frequently the ligand is a type of growth factor. One subfamily of kinases within this superfamily are the TAM subfamily of kinases, which comprise the tyrosine receptor kinases Axl, Tyro3 and Mer (Hafizi S and Dahlback B. Cytokine Growth Factor Rev 2006; 17: 295-304; Linger R M, et al. Adv Cancer Res 2008; 100: 35-83). This subfamily of kinases have in common a unique extracellular domain with N-terminal immunoglobulin domains and two fibronectin type III repeat structures. The structure of the fibronection type III repeats bears structural similarity to neural cell adhesion molecules (NCAMs). Although initially characterized as a single transmembrane protein, Axl can also exist as a soluble protein (sAxl) which is generated by ADAM10 (a metalloproteinase) mediated proteolysis. The role of sAxl is less well-characterized than intact, transmemberane Axl.
The natural ligand common to the TAM kinases is Gas6, a product of the growth arrest-specific gene 6 (Hafizi S and Dahlback B. FEBS J 2006; 273:5231-44; Bellido-Martin L and de Frutos P G. Vitam Horm 2008; 78:185-209.). The protein called protein S is also a potential natural ligand of the TAM kinases. Both of these proteins, Gas6 and protein S, are vitamin K-dependent proteins and share about 43% homology and several distinct protein domains. Binding of Gas6 to Axl leads to Axl autophosphorylation and activation of downstream signaling pathways including MAPK and PI3K/Akt pathways (Angelillo-Scherrer A, et al. J Clin Invest 2008; Shankar S L, et al. J Neuorosci 2006, 26: 5638-5648; Keating A K, et al. Oncogene 2006, 25:6092-6100), although the JAK/STAT pathway may be important for TAM-mediated immune responses (Rothlin C V, et al. Cell 2007, 131: 1124-1136).
The oncogenic potential of Axl was first discovered in chronic myelogenous leukemia (CML), but it has been demonstrated to play a role in the progression and metastasis of other cancer types. The increased expression of Axl and/or Axl ligand, Gash, has been shown in a number of human malignancies, including ovarian, melanoma, renal cell carcinoma, uterine leiomyoma, uterine endometrial cancer, thyroid carcinoma, gastric cancer, breast cancer, NSCLC, CML, AML, colorectal carcinoma, prostate cancer, various lymphomas, and esophageal cancer. The biochemical effects of increased expression of Axl is associated with increased oncogenic transformation, cell survival, proliferation, migration, angiogenesis, and cellular adhesion. Target validation studies of in vivo cancer models show that inhibition of Axl expression by RNAi blocked tumor growth in those models (e.g. see Li, Y. et al. Oncogene 2009, 28:3442-3455).
In addition to the association with cancer and tumorigenesis, TAM family kinases are implicated in a number of other cell and physiological functions. These include regulation of vascular smooth muscle homeostasis (Korshunov V A, et al. Hypertension 2007, 50: 1057-1062; Korshunov V A, et al. Circ Res 2006, 98: 1446-1452), platelet function, thrombus stabilization (Angelillo-Scherrer A, et al. J Clin Invest 2008, 118: 583-596; Gould W R, et al. J Thromb Haemost 2005, 3: 733-741), innate immunity (Lemke G and Rothlin CV. Nat Rev Immunol 2008, 8: 327-336) and inflammation (Rothlin C V, et al. Cell 2007, 131: 1124-1136; Sharif M N, et al. J. Exp Med 2006, 203: 1891-1901).
In summary, the Axl protein appears to have a key role in a number of human disorders, including cancer. The expression of the protein and/or the ligand is altered in these cancer cells. Thus, Axl protein is an attractive and valuable target for the discovery and development of new therapeutic agents to treat cancer and other conditions. There is a need for the design of specific and selective inhibitors for the treatment of disorders mediated and/or associated with Axl kinase.